Killing two birds with one stone—IL-4R target and IL-4/IL-13 dual blocking drug screening cell model
Background
IL-4 and IL-13 are both members of the interleukin family. IL-4 is mainly produced by activated CD4+ T cells, but can also be produced by NK cells, macrophages, eosinophils, basophils, mast cells and type 2 innate lymphocytes (ILC2). It can promote B cell proliferation, survival and conversion of immunoglobulins to IgG and IgE, promote the acquisition of Th2 phenotype by naive CD4+ T cells, promote the priming and chemotaxis of mast cells, eosinophils/basophils, and Activation of epithelial cell proliferation.
IL-13 is an immunomodulatory cytokine and a key ligand in the pathogenesis of allergic inflammation. Mainly secreted by activated TH2 cells, it can also be secreted by CD4+T cells, CD8+T cells, mast cells, basophils, eosinophils and NK cells. Promote Th2 cell differentiation, activate mast cells and eosinophils, induce the production and release of IgE, promote mucus production, promote fibroblast proliferation and collagen production, and participate in tissue fibrosis and remodeling processes.
Introduction to IL4 and IL13
IL-4 and IL-13 mainly exert their biological functions by binding to the IL-4R receptor complex. IL-4R mainly includes 2 types:
(1) Type I receptor is composed of IL-4R alpha subunit and gamma c subunit, and only binds IL-4;
(2) Type II receptor is composed of IL-4Rα subunit and IL-13Rα1 subunit and can bind IL-4 and IL-13.
After IL-4 binds to the type I receptor complex, it phosphorylates JAK1/3, thereby activating downstream STAT6 and IRS-2. STAT6 tyrosine phosphorylation promotes phospho-STAT6 homodimerization, nuclear translocation, and gene transcription. Tyrosine phosphorylation of IRS-2 leads to the activation of PI3-K, AKT, and NF-κB-driven gene transcription, further activating the cell cycle, proliferation, and survival.
Among type II receptors, the binding affinity of IL-4 to IL-4 Rα is higher than the binding affinity of IL-13 to IL-13 Rα1. Therefore, IL-4 and IL-13 bind to cells expressing type II receptors. There is competition. IL-4/IL-13 binds to type II receptors and activates downstream JAK1 and JAK2/TYK2, STAT6, STAT3 and STAT1, and subsequently activates related gene transcription.
IL-4R targets and diseases
1. Diseases related to type 2 inflammatory response: IL-4 and IL-13 are key cytokines in inducing and maintaining type 2 inflammatory response. Type 2 immune response mainly involves type 2 lymphocytes (ILC2) and type 2 helper T cells (Th2), secreting related cytokines (IL-4, IL-5, IL-13, IL-25, IL-31, A general term for a large class of diseases caused by increased expression of IL-33, TSLP, etc., including atopic dermatitis, allergic rhinitis, asthma, food allergy and other diseases. In the pathogenesis of such allergic diseases, Th2 plays a key role, IL-4/13 is in a central position, and IL-4Rα is a common subunit of IL-4 and IL-13 receptors, so the IL-4R target It has become an important target for the treatment of diseases related to type 2 immune response. By targeting IL-4Rα, double blocking of IL-4 and IL-13 can block intracellular signal transduction, thereby inhibiting Th2 cell differentiation, IgE synthesis and inflammatory substance secretion, thereby regulating immune function and achieving the purpose of killing two birds with one stone. .
2. Tumors: Multiple studies have shown that cell cultures from B-cell chronic lymphocytic leukemia patients contain high levels of IL-4, which is synthesized by costimulatory T cells or B-cell chronic lymphocytic leukemia cells, and contributes to the in vitro progression of tumor B cells. and growth are important. Research and development in recent years have found that IL-4R is overexpressed in many epithelial cancers and is a promising target for metastatic tumor treatment. IL-4/IL-4R signaling on epithelial cancer cells directly affects tumor biology. According to scientific research progress, targeting IL-4 or IL-4R to inhibit the growth of metastatic tumors is a potential treatment.
3. Inflammatory arthritis: Inflammatory arthritis constitutes a group of various rheumatic diseases characterized by inflammation of the synovial joints as well as systemic manifestations. Rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS) are the most common subtypes of inflammatory arthritis. A large number of studies have shown that IL-4/IL-13 cytokines are involved in reducing the production of pro-inflammatory cytokines (IL-1β, IL-6, IL-8, TNF) and metalloproteinases. Therefore, the IL-4R target is also a potential therapeutic target for inflammatory arthritis.
Current status of IL-4R target drug development
Dupilumab (Dupixent®) is a fully human monoclonal antibody against IL-4Rα jointly developed by Sanofi and Regeneron. It has been approved for atopic dermatitis (AD), asthma, and chronic sinusitis with rhinitis. With 5 indications including polyposis, eosinophilic esophagitis (EoE), and prurigo nodularis (PN), sales in 2021 have reached US$6.4 billion. In addition, domestic and foreign companies still have many pipelines in the clinical stage, mainly focusing on the two major fields of asthma and AD. New indications and clinical applications may continue to emerge in the future.
IL-4R target drug cell screening model
In response to the needs of IL-4R target and IL-4 and IL-13 dual blocking drug development research needs, we have developed the hIL4/IL13 Dual Effector Reporter Cell drug screening cell model. Welcome to inquire. Some data are shown below:
hIL4/IL13 Dual Effector Reporter Cell RQP74110
Figure 4. Dose Response of Recombinant Human lL13 in Human hlL4/IL13 Dual Effector Reporter Cells.
Figure 5. Dose Response of Recombinant Human lL4 in hlL4/IL13 Dual Effector Reporter Cells (C7).
Figure 6. Inhibition of IL-4-induced Reporter Activity by IL-4R Neutralizing Antibody in hIL4/IL13 Dual Effector Reporter Cells (Clone 7).
Figure 7. lnhibition of IL-13-induced Reporter Activity by IL-4R Neutralizing Antibody in hIL4/IL13 Dual Effector Reporter Cells.
